Corona virus research: enzyme boosts virus replication

Scientists at Goethe University Frankfurt have discovered a potential target for new anti-SARS CoV-2 drugs. According to a publication in Nature a papain-like protease (PLpro), which stimulates the virus multiplication in cells and at the same time weakens the immune defense of the infected.

“When the SARS-CoV-2 virus penetrates human cells, it allows its own proteins to be produced by the human host cell. One of these virus proteins called PLpro is essential for the multiplication and rapid spread of the virus,” it said in a broadcast the Goethe University. The work was carried out with international cooperation and with the help of the Frankfurt University Hospital. The main result: inhibition of this viral enzyme by medication not only blocks virus multiplication, but also strengthens the antiviral immune response.

Different defense mechanisms

When infected, the SARS-CoV-2 virus has to overcome various defense mechanisms in the human body. This includes the unspecific or innate immune defense. Affected body cells release messenger substances, so-called type I interferons. These attract natural killer cells, which kill the infected cells. One of the reasons why the SARS-CoV-2 virus is so successful – and therefore dangerous – is because it can suppress the non-specific immune response.

The scientists: “For this purpose, the human cell allows the virus protein PLpro (papain-like protease) to be produced. PLpro has two functions: it helps in the maturation and release of new virus particles and it suppresses the formation of type I interferons. The German and Dutch scientists have now been able to observe these processes in cell culture experiments.

“Double strike strategy”

Ivan Dikic, director of the Institute of Biochemistry II at the University Hospital Frankfurt and last author of the thesis, explains: “We used the active ingredient GRL-0617, an inhibitor of PLpro, and its mode of action was examined biochemically, structurally and functionally. We came to the conclusion that inhibition of PLpro is a promising therapeutic ‘double strike’ strategy for the treatment of Covid-19.

The further development of PLpro-inhibiting substance classes for use in clinical studies is now a central challenge for this therapeutic approach. “Apparently SARS-CoV-2 suppresses the body’s own interferon-I production more than SARS pathogens, which after their sudden appearance around the turn of the millennium disappeared again.

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